Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes.
Since the introduction of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glycemia levels, diabetic patients often practice multiple daily injection therapy, whereby monomeric insulin is administered with each meal and acylated or intermediate acting insulin is administered once or twice daily to cover the basal need.
In the treatment of diabetes mellitus, many varieties of insulin formulations have been suggested and used, such as regular insulin, isophane insulin (designated NPH), insulin zinc suspensions (such as Semilente®, Lente®, and Ultralente®), and biphasic isophane insulin. As diabetic patients are treated with insulin for several decades, there is a major need for safe and life quality improving insulin formulations. Some of the commercial available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action. Fast-acting insulin formulations are usually solutions of insulin, while retarded acting insulin formulations can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both. In addition, some patients are using formulations having both a fast onset of action and a more prolonged action. Such a formulation may be an insulin solution wherein protamine insulin crystals are suspended. Some patients do themselves prepare the final formulation by mixing an insulin solution with an insulin suspension formulation in the ratio desired by the patient in question.
Human insulin consists of two polypeptide chains, the so-called A and B chains which contain 21 and 30 amino acid residues, respectively. The A and B chains are interconnected by two cystine disulphide bridges. Insulin from most other species has a similar construction, but may not contain the same amino acid residues at the same positions.
The development of the process known as genetic engineering has made it possible to prepare a great variety of insulin compounds being analogous to human insulin. In these insulin analogues, one or more of the amino acids have been substituted with other amino acids which can be coded for by the nucleotide sequences.
Normally, insulin formulations are administered by subcutaneous injection. What is important for the patient, is the action profile of the insulin formulation which is the action of insulin on the glucose metabolism as a function of the time from the injection. In this profile, inter alia, the time for the onset, the maximum value, and the total duration of action are important. A variety of insulin formulations with different action profiles are desired and requested by the patients. One patient may, on the same day, use insulin formulations with very different action profiles. The action profile requested is, for example, depending on the time of the day and the amount and composition of any meal eaten by the patient.
Stable insulin formulations are particularly required for use in delivery devices that expose these agents to elevated temperatures and/or mechanical stress. For example, stable insulin formulations are required for use in continuous infusion systems and pen delivery devices.
There is a need for new ways of stabilizing since a stablizer, Genapol® (poloxamer 171), which for a long period of time has been used for stabilizing human insulin for pumps, may have some undesired effects (see Diabetes Metab. 26 (2000), 304-306).
In continuous infusion systems, a fluid containing an insulin formulation is pumped from a reservoir, usually to a subcutaneous, intravenous, or intraperitoneal depot. The reservoir, which must be exchanged or refilled periodically, is attached to the patient's body, or implanted into the patient's body. In either case, the patient's body heat and body motion, plus turbulence in the tubing and pump impart a relatively high amount of thermo-mechanical energy to the formulation. In the interest of minimizing the frequency with which the reservoir is filled, and of minimizing the size of the reservoir, formulations having a relatively high concentration of insulin are highly advantageous. It is desirable to have insulin formulations which are stable for at least one month under stressful in-use conditions.
Formulations of insulin for use in continuous infusion systems must remain soluble and substantially free of aggregation, even though subjected to the patient's body heat and motion for periods ranging from a few days to several months. Instability is promoted by the thermo-mechanical stress to which formulations are exposed in continuous infusion systems. Therefore, improvements in the physical stability of concentrated insulin formulations is urgently needed to permit them to be used successfully in continuous infusion systems.
It has become usual to use monomeric insulins in pumps. However, compared with human insulin, monomeric insulins have an increased tendency to form insoluble fibrils.
Among others, there are two major problems in connection with the use of insulin formulations in a continuous infusion system:    1. Due to fibrillation of the insulin component, the catheter may clog, and    2. There is a risk of fast development of ketoacidosis which may be fatal. Ketoacidosis may result from discontinuation of insulin delivery, for example due to fibrillation, pump failure, or the patient forgetting to reapply the pump after disconnection.
According to U.S. Pat. No. 4,476,118, pharmaceutical solutions of dissolved insulin having improved physical stability can be prepared by using ionized zinc salts. These solutions are particularly adapted for use in continuous insulin delivery equipment.
According to U.S. Pat. No. 4,472,385, pharmaceutical solutions of dissolved insulin having improved physical stability particularly adapted for use in continuous insulin delivery equipment can be by using a calcium or magnesium salt.
According to U.S. Pat. No. 4,614,730, insulin solutions may be stabilized by using a phospholipid.
According to U.S. Pat. No. 5,866,538, insulin formulations of superior chemical stability can be obtained in the presence of glycerol and/or mannitol and rather low halogenide concentrations.